SOLID DOSAGE FORM OF RIVAROXABAN AND METHODS FOR MAKING THE SAME

Abstract

The present invention discloses a pharmaceutical composition that includes rivaroxaban and one or more excipient in a solid dosage form and methods for making the same. Methods for making compositions of the present invention includes powderizing rivaroxaban by centrifugal wet granulation to form compositions suitable for solid oral dosage form. Pharmaceutical dosage forms produced by methods of the present invention are more homogenous, smoother, and have better rheological properties, better compressibility, and much easier to make. They are much lower in cost and also easier to produce at industrial scales.

Claims

1. A method for preparing a composition comprising rivaroxaban and one or more excipients, said comprising: forming an oral dosage form comprising micronized rivaroxaban using centrifugal wet granulation; wherein said dosage form is suitable as a solid oral pharmaceutical composition.

2. The method of claim 1, wherein said method is performed by a centrifugal granulator.

3. The method of claim 2, wherein said granulator comprises a rotary base, an air ventilation and heating device, and said rotary base rotates at a rate of about 0 to about 1000 rpm during operation.

4. The method of claim 2, wherein said granulator further comprises one or more atomizing nozzle.

5. The method of claim 1, wherein said 90% of resulting rivaroxaban has a diameter less than 50 micrometer.

6. The method of claim 1, wherein the excipient comprise at least one disintegrating agent.

7. The method of claim 1, wherein the excipient comprises at least one thinning agent.

8. The method of claim 1, wherein the excipient comprises the combination of: at least one thinning agent, and at least one disintegration agent; at least one thinning agent, and at least one adhesive agent; or at least one thinning agent, at least one disintegrating agent, or at least one adhesive agent.

9. The method of claim 1, wherein said solid oral pharmaceutical composition comprises crystalline form of rivaroxaban.

10. A solid oral pharmaceutical obtained according to the method of claim 1.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0034] FIG. 1 shows exemplary dissolution curves of pharmaceutical compositions in accordance with the different embodiments of the present invention. The dissolution test is performed in a solution containing 0.5% SLS (sodium lauryl sulfate) and pH 4.5 acetic acid-sodium acetate buffer.

[0035] FIG. 2 shows exemplary dissolution curves of pharmaceutical compositions in accordance with the different embodiments of the present invention in water.

[0036] FIG. 3 shows exemplary dissolution curves of pharmaceutical compositions in accordance with the different embodiments of the present invention in 0.1 mol/L of hydrochloric acid solution.

[0037] FIG. 4 shows exemplary dissolution curves of pharmaceutical compositions in accordance with the different embodiments of the present invention in a pH .5 acetic acid-sodium acetate buffer solution.

[0038] FIG. 5 shows exemplary dissolution curves of pharmaceutical compositions in accordance with the different embodiments of the present invention in a pH 6.8 phosphate buffer.

DETAILED DESCRIPTION

[0039] The present invention will now be described in detail by referring to specific embodiments as illustrated in the accompanying figures.

[0040] To further illustrate the present invention, the following specific examples are provided

EXAMPLES

Example 1

Manufacturing of 20.0 mg Rivaroxaban Tablets Using Centrifugal Granulation

[0041] 1.1. Tablet Ingredients (Mg/Tablet)

TABLE-US-00002 Rivaroxaban (micronized) 20.0 mg Microcrystalline cellulose 36.0 mg Lactose 23.4 mg Cross-linked sodium carboxymethyl cellulose 3.0 mg Hydroxypropylmethylcellulose, 5 cp 1.5 mg Sodium dodecyl sulfate 0.5 mg Magnesium stearate 0.6 mg enteric-coating material 2.5 mg

[0042] 1.2 Preparation:

[0043] Dissolve Hydroxypropylmethylcellulose (5 cp) and Sodium dodecyl sulfate in water. Stir the mixture while adding micronized rivaroxaban. After all rivaroxaban is added, thoroughly mix to form a suspension. Introduce Microcrystalline cellulose, lactose, Cross-linked sodium carboxymethyl cellulose into centrifugal granulator. Set rotary speed to between 100-500 rpm. Air temperature to between 5080 C., ventilation frequency between 10.020.0 Hz, air venting frequency to between 20.030.0 Hz, atomizing pressure to between 0.51.5 bar, peristaltic pump rotation rate to between 520 rpm. Turn on the granulator and set initial granulator pre-heating temperature to 30 C., then initiate atomization and peristaltic pump to atomize the rivaroxaban suspension at a constant speed until all suspension is atomized. Turn off the atomizer and peristaltic pump. Allow the preparation material to dry until reaching 40 C. Then, discharge the preparation, pelletize and add Magnesium stearate to the mixture and thoroughly mix. Compress the resulting mixture to form 6 mm diameter tablets with breaking strength between 50-100N. Apply enteric coating to form the final tablet.

Example 2

Manufacturing of 15.0 mg Rivaroxaban Tablets Using Centrifugal Granulation

[0044] 2.1 Tablet Ingredients (Mg/Tablet)

TABLE-US-00003 Rivaroxaban (micronized) 15.0 mg Microcrystalline cellulose 38.5 mg Lactose 25.9 mg Cross-linked sodium carboxymethyl cellulose 3.0 mg Hydroxypropylmethylcellulose, 5 cp 1.5 mg Sodium dodecyl sulfate 0.5 mg Magnesium stearate 0.6 mg enteric-coating material 2.5 mg

[0045] 2.2 Preparation:

[0046] Dissolve Hydroxypropylmethylcellulose (5 cp) and Sodium dodecyl sulfate in water. Stir the mixture while adding micronized rivaroxaban. After all rivaroxaban is added, thoroughly mix to form a suspension. Introduce microcrystalline cellulose, lactose, Cross-linked sodium carboxymethyl cellulose into centrifugal granulator. Set rotary speed to between 100-500 rpm. Air temperature to between 5080 C., ventilation frequency between 10.020.0 Hz, air venting frequency to between 20.030.0 Hz, atomizing pressure to between 0.51.5 bar, peristaltic pump rotation rate to between 520 rpm. Turn on the granulator and set initial granulator pre-heating temperature to 30 C. Then, initiate atomization and peristaltic pump to atomize the rivaroxaban suspension at a constant speed until all suspension is atomized. Turn off the atomizer and peristaltic pump. Allow the preparation material to dry until reaching 45 C. Then, discharge the mixture, pelletize and add Magnesium stearate to the mixture and thoroughly mix. Compress the resulting mixture to form 6 mm diameter tablets with breaking strength between 50-100N. Apply enteric coating to form the final tablet.

Example 3

Manufacturing 20.0 mg of Rivaroxaban Tablet Using High Shear Wet Granulation

[0047] 3.1 Tablet Ingredients (Mg/Tablet)

TABLE-US-00004 Rivaroxaban (micronized) 20.0 mg Microcrystalline cellulose 36.0 mg Lactose 23.4 mg Cross-linked sodium carboxymethyl cellulose 3.0 mg Hydroxypropylmethylcellulose, 5 cp 1.5 mg Sodium dodecyl sulfate 0.5 mg Magnesium stearate 0.6 mg enteric-coating material 2.5 mg

[0048] 3.2 Preparation:

[0049] Dissolve Hydroxypropylmethylcellulose (5 cp) and Sodium dodecyl sulfate in water. Stir the mixture while adding micronized rivaroxaban. After all rivaroxaban is added, thoroughly mix to form a suspension. Introduce Microcrystalline cellulose, lactose, Cross-linked sodium carboxymethyl cellulose into high shear wet granulator. Set stirring rod speed to 250 rpm, shearing knife speed to 600 rpm, atomization pressure to 1.0 bar, peristaltic pump rotation speed to 20 rpm. Turn on the high shear wet granulator for 5 min, then, turn on atomizer and peristaltic pump to inject the suspension at a constant rate until all suspension is used up. Turn off atomizer and peristaltic pump. Quickly transfer the wet pellets to fluidized bed for drying. Set the air temperature of the fluidize bed to 65 C., ventilation frequency to 25.0 Hz, and begin drying until reaching 42 C. Then, take out the pellet, add magnesium stearate to the mixture and thoroughly mix. Compress the resulting mixture to form 6 mm diameter tablets with breaking strength between 50-100N. Apply enteric coating to form the final tablet.

Example 4

Manufacturing of 20.0 mg Rivaroxaban Tablets Using Direct Compression

[0050] 4.1 Tablet Ingredients (Mg/Tablet)

TABLE-US-00005 Rivaroxaban (micronized) 20.0 mg Microcrystalline cellulose 36.0 mg Lactose 23.4 mg Cross-linked sodium carboxymethyl cellulose 3.0 mg Hydroxypropylmethylcellulose, 5 cp 1.5 mg Sodium dodecyl sulfate 0.5 mg Magnesium stearate 0.6 mg enteric-coating material 2.5 mg

[0051] 4.2 Preparation:

[0052] Thoroughly mix Sodium dodecyl sulfate with rivaroxaban powder. Then add microcrystalline cellulose, lactose, hydroxypropylmethylcellulose (5 cp) and cross-linked sodium carboxymethyl cellulose. Mix thoroughly and then finally add Magnesium stearate and mix thoroughly. Then, compress the resulting mixture to form 6 mm diameter tablets with breaking strength between 50-50N. Apply enteric coating to form the final tablet.

Example 5

Manufacturing 20.0 mg Rivaroxaban Tablets With Fluidized Bed

[0053] 5.1 Tablet Ingredients (Mg/Tablet)

TABLE-US-00006 Rivaroxaban (micronized) 20.0 mg Microcrystalline cellulose 36.0 mg Lactose 23.4 mg Cross-linked sodium carboxymethyl cellulose 3.0 mg Hydroxypropylmethylcellulose, 5 cp 1.5 mg Sodium dodecyl sulfate 0.5 mg Magnesium stearate 0.6 mg enteric-coating material 2.5 mg

[0054] 5.2 Preparation:

[0055] Dissolve Hydroxypropylmethylcellulose (5 cp) and Sodium dodecyl sulfate in water. Stir the mixture while adding micronized rivaroxaban. After all rivaroxaban is added, thoroughly mix to form a suspension. Introduce Microcrystalline cellulose, lactose, Cross-linked sodium carboxymethyl cellulose into fluidized bed granulator. Set air temperature to 65 C., ventilation frequency to 20.0 Hz, atomizing pressure to 0.5 bar, peristaltic pump speed to 5 rpm. Set pre-heating temperature to 35 C., then turn on peristaltic pump to begin injecting and atomizing then suspension at a constant rate until all suspension is used up. Turn off the atomizer and peristaltic pump. Allow mixture to continue drying until reaching 50 C. Remove the material from the granulator, add magnesium stearate to the mixture and thoroughly mix. Compress the resulting mixture to form 6mm diameter tablets with breaking strength between 50-100N. Apply enteric coating to form the final tablet.

Example 6

Comparison of Rivaroxaban Granules Made by Different Preparation Methods

[0056] 6.1 Comparing Shape, Diameter, Flowability, and Compressibility

[0057] Because preparation of Example 1 and 2 have very similar properties, they will be averaged and compared to the preparations of Examples 3 and 5.

TABLE-US-00007 flowability ( repose Compressibility Prep Method Shape Diameter angle ) ( Carr's index ) Fluidized bed Near spherical not Wide spread 36.5 22.1 ( Ex. 5 ) round enough more fine powder porous High shear Near spherical not Wide spread 36.9 20.8 ( Ex. 3 ) round enough few fine powder non-porous Centrifugal spherical non- Narrow spread 33.1 18.2 ( Ex. 1 or 2 ) porous few fine powder uniform

[0058] 6.2 Comparison of Yield

TABLE-US-00008 Prep method Yield Fluidized bed ( Ex. 5 ) 88.2% High shear ( Ex. 3 ) 86.2% Centrifugal ( Ex.1 or 2 ) 94.5%

Example 7

Comparison of Tablets Made by Different Methods

[0059] 7.1 Breaking Strength (Huanghai Medicine & Drug, YPD-300C Tablet Hardness Tester) [0060] Example 1 tablet: 62N [0061] Example 2 table: 63N [0062] Example 3 tablet: 60N [0063] Example 4 tablet: 43N [0064] Example 5 tablet: 58N

[0065] 7.2 Disintegration Time (Pharmacopoeia of the People's Republic of China 2010, Part 2, Appendix X A Disintegration Testing Method).

[0066] Example 1 tablet: 5.1 min

[0067] Example 2 tablet: 5.2 min

[0068] Example 3 tablet: 6.3 min

[0069] Example 4 tablet: 2.0 min

[0070] Example 5 tablet: 5.5 min

[0071] 7.3 In Vitro Dissolution Test

[0072] Dissolution method (Pharmacopoeia of the People's Republic of China 2010, Part 2, Appendix X C Dissolution Method 2)

[0073] Stirring rod speed: 75 rpm

[0074] Dissolution medium: [0075] 1) 0.4% Sodium dodecyl sulfate, pH 4.5 acetic acid-sodium acetate buffer [0076] 2) Water [0077] 3) 0.1 mol/L hydrochloric acid [0078] 4) pH 4.5 acetic acid-sodium acetate buffer [0079] 5) pH 6.8 phosphate buffer

[0080] Dissolution medium temperature: 37 C.0.5 C.

[0081] Detection method: HPLC (Pharmacopoeia of the People's Republic of China 2010, Part 2, Appendix IV D)

[0082] Detection wavelength: 250 nm

[0083] Calculation method: external standard

[0084] Reference dissolved solution: weigh accurately amount of rivaroxaban, add 50% acetonitrile, then dilute with dissolution medium to 25 g/ml solution.

[0085] Use 6 tablets from each Example. Take sample at 5 min, 10 min, 15 min, 20 min, 30 min, 45 min, 60 min intervals and refill medium accordingly. Filter the sample and determine concentration. The following table shows the result:

TABLE-US-00009 5 min 10 min 15 min 20 min 30 min 45 min 60 min Ex. 1 40.2% 86.5% 94.8% 95.0% 95.2% 97.3% 97.7% Ex. 2 73.9% 88.6% 94.5% 94.9% 95.3% 96.9% 97.1% Ex. 3 38.2% 80.2% 85.1% 86.0% 86.9% 89.1% 88.7% Ex. 4 37.6% 81.4% 86.9% 87.1% 87.3% 88.6% 88.4% Ex. 5 38.8% 85.2% 90.1% 91.5% 91.2% 92.3% 92.5%

[0086] In addition, dissolutions of Example 1, 2 and 5 tablets in water, 0.1 mol/L hydrochloric acid, pH 4.5 acetic acid-sodium acetate buffer, and pH 6.8 phosphate buffer were also determined. Results are shown in FIGS. 2-5.

[0087] The above results show that solid dosage form of rivaroxaban obtained by centrifugal wet granulation method as disclosed in the present invention exhibits superior properties as a pharmaceutical formulation, particularly in simulated enteric environment, and is suitable for oral dosage form.

[0088] Although the present invention has been described in terms of specific exemplary embodiments and examples, it will be appreciated that the embodiments disclosed herein are for illustrative purposes only and various modifications and alterations might be made by those skilled in the art without departing from the spirit and scope of the invention as set forth in the following claims.